Modern family planning depends on the availability of contraceptive methods. At present, the major burden of fertility regulation is carried by women since most available methods are female methods. Oral contraceptives, implants and injectables intrauterine devices, tubal ligation, diaphrams, and spermicides are all methods practiced by females.
Methods for controlling male fertility have been known for centuries, but social science research on such methods has existed for only about twenty years, coinciding roughly with the widespread introduction of vasectomy. See Ringheim, Studies In Family Planning 24(2): 87-99 (1993). Currently available methods, however, have several drawbacks. For example, although vasectomy is one of the most prevalent methods in the United States, Australia, and New Zealand, it remains little used elsewhere, partially because the difficulty and expense of reversal still limit the appropriateness of the technique to those wishing to stop rather than space child bearing, and the method's irreversibility remains the biggest obstacle to its acceptability. Id. The vas occlusion method utilizing a silicone plug, and other methods of occluding the vas that are currently undergoing clinical trials may only be somewhat more acceptable than vasectomy, unless they are easily reversible. Id. The slow progress in the development of male contraceptives has been due in part to the relative complexity of the male reproductive system. Id.
Evidence is forthcoming that a drug-based male contraceptive would be acceptable in many countries. However, controlling male reproduction by interfering with the spermatogenic process has been a much more difficult task to achieve than inhibiting ovalation. See World Health Organization, "Challenges in reproductive health research," Biennial Report 1992-1993. In particular, research has focused on a selection of a variety of hormonal drugs that can effectively suppress pituitary hormone secretion. For instance, several small trials involving GnRH antagonists have provided evidence that these drugs effectively suppress the release of gonadotrophins and render a significant proportion of men azoospermic (i.e., the complete absence of sperm from the ejaculate). However, the current generation of antagonists do not have sufficient biological potency and thus can not be considered for further development, since in order to attain the desired level of efficacy too much compound will be needed, which will be to expensive. Id. A number of substances are also known to effect male fertility via a direct interference with the process of spermatogenesis. Unfortunately, research on most of the substances has not gone beyond pre clinical studies because of toxicity or because undesirable side-effects were observed in animals. Id.
In view of the readiness of men to accept new male contraceptive methods is underlined by repeated opinion polls. See, e.g., Konig U., Revolution bei der Verhutung: J etzt sind die Manner dran. Stern 24/91:28-34 (1991). Research to develop safe, effective, reversible and acceptable methods of fertility regulation for men has thus been supported by several international agencies, many national research counsels, and some pharmaceutical companies. Accordingly, not only a long-term need remains not only for the development of safe and effective male contraceptives, but also a short term need for the development of a means to screen large numbers of substances to identify and evaluate potential contraceptive agents.
Spermatogenesis is a terminal differentiation process whereby male germ cells develop into mature spermatozoa. Leblond, et al., Ann. N.Y. Acad. Sci. 55:548-573 (1952); Parvinen, M., Endocr. Rev. 3:404-417 (1982). Primordial germ cells, derived from primitive ectoderm, are established in the primitive gonad on embryonic day 10.5 in the mouse. After birth these cells proliferate extensively giving rise to type A spermatogonia which can either replicate as stem cells or differentiate to type B spermatogonia. At puberty type B spermatogonia develop into large diploid primary spermatocytes that undergo two reductive divisions, giving rise to the haploid spermatids. Spermatids evolve into mobile spermatozoa through a process referred to as spermiogenesis, characterized by restructuring of their nuclei and development of flagella. An essential component of spermiogenesis is meiosis, a process that involves a single round of DNA replication, pairing and recombination, followed by two reductive divisions. See Parvinen, supra. Although meiotic reduction has been extensively studied in yeast (reviewed in McLeod, BioAssays 11:9-14(1989), much less is known of the regulatory factors that may be involved in meiosis in mammals.
Molecular cloning of the mammalian DNA-binding proteins Oct-1, Oct-2 and Pit-1, and the C. elegans developmental regulatory gene unc-86, revealed that all had a common sequence referred to as the POU-domain, which is required for high affinity DNA-binding and protein-protein interactions. Herr, et al., Genes Dev. 2:1513-1516 (1988). The POU-domain is a bipartite structure comprised of the POU-specific domain, which is connected by a short variable linker sequence to the POU homeodomain. Subsequently, several new members of this gene family, most of which are predominantly expressed in the developing and adult nervous system, have been described in mammals. See Ruvkun, et al., Cell 64:475-478 (1991); Rosenfeld, et al., Genes Dev. 5:897-907 (1991); and Scholer, Trends Genes. 7:323-329 (1991). Notable exceptions to this expression pattern are provided by Oct-1, Sturm, et al., Genes Dev. 2:1582-1599 (1988); and Brn-5, Andersen, et al., Biol. Chem. 268, in press (1993) that have widespread distribution; Pit-1, Oct-2 and Skn-1a/i that are expressed in the anterior pituitary, Ingraham, et al., Cell 55:519-529 (1988); B lymphocytes, Clerc, et al., Genes Dev. 2:1570-1582 (1988), and skin, Andersen, et al., Science 260:78-82 (1993), respectively; and Oct-3/4 that is expressed in undifferentiated cells early in development and later becomes restricted to oocytes, Okamoto, et al., Cell 60:461-472 (1990); Scholer, et al., Nature (London) 344:435-439 (1990); Rosner, et al., Nature (London) 345:686-692 (1990); and Scholer, et al., EMBO J. 9:2185-2195 (1990).
Genetic evidence indicates that Oct-2, Pit-1 and unc-86 are required for cell determination and/or function in B lymphocytes (Corcoran, et al., Genes Dev. 7:570-582 (1993)), anterior pituitary (Li, et al., Nature (London) 347:528-533 (1990)), and sensory neurons (Finney, et al., Cell 63:895-905 (1990)). Although the functions of other POU proteins remain elusive, the present evidence suggests that many members of this family may have important roles in cell specification and terminal differentiation.